A Minimal Circadian Clock Network for Glucose Tolerance in Mice

Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by this interconnectedness is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism – liver and skeletal muscle – by rescuing clock function either in each organ separately, or in both organs simultaneously, in otherwise clock-less mice. Experiments revealed that individual clocks are partially sufficient for tissue glucose metabolism, yet the connections between both tissue clocks coupled with daily feeding rhythms maximizes systemic glucose tolerance. This synergy relies in part on local transcriptional control of the glucose machinery, feeding-responsive signals such as insulin, and metabolic cycles that connect the muscle and liver. We posit that spatiotemporal mechanisms of muscle and liver play an essential role in the maintenance of systemic glucose homeostasis, and that disrupting this diurnal coordination can contribute to the metabolic disease. Gastocnemius muscle and livers were harvested from WT, Bmal1-KO, Liver-RE, Muscle-RE and Liver+Muscle-RE mice after 2 weeks of food access only during the 12 hour dark phase. Bulk RNA-seq was performed on harvested tissues. ZT refers to time in hours since the start of the 12 hour light dark cycle.